Immunomodulation PDF

ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Immunomodulation Pedro Bittencourt DVM, MSc, PhD ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Learning Objectives Define Immunomodu...

ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Immunomodulation Pedro Bittencourt DVM, MSc, PhD ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Learning Objectives Define Immunomodulation Describe the different types of immunomodulatory agents Discuss immunosuppression - Non-specific vs. Selective Discuss immunopotentiation 2 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Immunomodulation Use of agents to potentiate or suppress the immune response Immunosuppression – dampening the immune response Non-specific Selective Immunopotentiation - stimulation of the immune response 3 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Non-specific immunosuppression Radiation – Prevents cell division – DNA damage Cell cycle arrest (G1/S checkpoint) 4 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Non-specific immunosuppression Corticosteroids – Stimulates synthesis of IκBα (inhibitor of NF-κB) – Blocks cytokines synthesis and T cell responses – Both anti inflammatory and immunosuppressive 5 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE 6 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Non-specific immunosuppression Cytotoxic drugs – Alkylating agents (Cyclophosphamide) Cross-link DNA preventing cell division – Folic acid antagonists (Methotrexate) Blocks production of tetrahydrofolate, necessary for thymidine and purine nucleotides synthesis – DNA synthesis inhibitors (Azatiophrine) Inhibits DNA and RNA synthesis 7 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Selective immunosuppression Calcineurin inhibitors – Cyclosporine Forms complex with cyclophilin and blocks calcineurin – Tacrolimus Forms complex with immunophilin and blocks calcineurin – Inhibits IL-2 synthesis 8 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Selective immunosuppression Rapamycin (Sirolimus) – Forms complex with immunophilin and blocks mTOR (mechanistic Target Of Rapamycin) – mTOR is a regulator of cell metabolism, growth, proliferation and survival 9 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE 10 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Selective immunosuppression JAK (Janus kinase) inhibitors JAK-STAT signaling Immunity Cell division Cell death 11 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Selctive immunosuppression JAK (Janus kinase) inhibitors Oclacitinib (Apoquel) Inhibits mainly JAK1 Treatment for atopic dermatitis JAK1 dependent cytokines: IL-2, IL-4, IL-6, IL-13, IL-31 12 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE Stimulation of the Immune System Bacterial products – Bacille Calmette-Guerin (Mycobacterium bovis) – Source of PAMPs, TLR stimulation, cytokine synthesis Complex carbohydrates – Zymosan, Glucans, Lentinans, aminated polyglucose – Activates macrophages Vitamins – A, D, and E Cytokines – IL-2, recombinant IFNs (α & γ) 13 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE BCG vaccine induces enhanced production of pro-inflammatory cytokines, such as IL-1β,TNF-α, and IL-6. Effects are accompanied by transcriptional, epigenetic and metabolic reprogramming of the myeloid cells in the BCG-vaccinated individuals “Trained immunity” 14 ROSS UNIVERSITY SCHOOL OF VETERINARY MEDICINE